Abstract
USP25 deubiquitinating enzyme is a key member of the ubiquitin system, which acts as a positive regulator of the Wnt/β-catenin signaling by promoting the deubiquitination and stabilization of tankyrases. USP25 is characterized by the presence of a long insertion in the middle of the conserved catalytic domain. The crystal structure of USP25 displays an unexpected homotetrameric quaternary assembly that is directly involved in the inhibition of its enzymatic activity. The tetramer is assembled by the association of two dimers and includes contacts between the coiled-coil insertion domain and the ubiquitin-binding pocket at the catalytic domain, revealing a distinctive autoinhibitory mechanism. Biochemical and kinetic assays with dimer, tetramer and truncation constructs of USP25 support this mechanism, displaying higher catalytic activity in the dimer assembly. Moreover, the high stabilization of tankyrases in cultured cells by ectopic expression of a constitutive dimer of USP25 supports a biological relevance of this tetramerization/inhibition mechanism.
Highlights
USP25 deubiquitinating enzyme is a key member of the ubiquitin system, which acts as a positive regulator of the Wnt/β-catenin signaling by promoting the deubiquitination and stabilization of tankyrases
Two remarkable features are obtained from the crystal structure of USP25: the presence of two different stable quaternary assemblies, tetramer and dimer; and the implication of these two oligomer states in the deubiquitinating activity of USP25 by a unique autoinhibitory mechanism
This tetramerizationdependent inhibition mechanism of USP25 has never been described for other members of the deubiquitinating enzymes (DUBs) family and might represent a paradigmatic example of regulation of the deubiquitinating activity, as we demonstrated in vitro and in cultured cells with the stabilization of tankyrases
Summary
USP25 deubiquitinating enzyme is a key member of the ubiquitin system, which acts as a positive regulator of the Wnt/β-catenin signaling by promoting the deubiquitination and stabilization of tankyrases. Structural studies show that USPs have a common conserved fold consisting of three subdomains known as Palm, Thumb, and Fingers, in which the active site cysteine is located between the Palm and Thumb, while the Fingers grip the “distal” ubiquitin[10]. Their catalytic activities are usually modulated through their different additional domains. It has been shown that USP25 directly interacts with tankyrases through its C-terminal tail and promotes their deubiquitination and stabilization, regulating Wnt/β-catenin signaling pathway, making an important impact in cell proliferation and human cancer development[28]
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